US2004176366A1PendingUtilityA1
Method of preventing or treating atherosclerosis or restenosis
Est. expiryAug 30, 2022(expired)· nominal 20-yr term from priority
A61K 31/33A61K 31/401A61K 31/421A61K 31/426A61K 31/4375A61K 31/445A61K 31/47A61K 31/495A61K 31/502A61K 31/503A61K 31/537A61K 31/54
49
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Claims
Abstract
The present invention provides a method of preventing or treating atherosclerosis or restenosis in mammals, which comprises administering an effective amount of a compound selected from the group consisting of structures of Formulas X and XII-XV: wherein the substituent groups are as defined herein.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of preventing or treating atherosclerosis or restenosis in a mammal, comprising administering to said mammal an effective amount of a compound selected from the group consisting of structures of Formula X, Formula XII, Formula XIII, Formula XIV and Formula XV,
wherein Formula X is
and pharmaceutically acceptable salts thereof; and
wherein ring A is a saturated or unsaturated fused double or triple heterocyclic ring having 1, 2, 3 or 4 heteroatoms selected from group consisting of oxygen, sulfur, or nitrogen; and
wherein R and Xx are the appropriated substitutents, respectively;
wherein Formula XII is
wherein,
X XII is Cl, Br, F, CN or NO 2 ;
G XII is
a) C 1-7 alkyl which partially unsaturated and is substituted by hydroxy, or
b) C 1-4 alkyl substituted by NR XII-1 R XII-2 or 4-tetrahydropyran;
R XII-1 is C 2-7 alkyl substituted by hydroxy, C 1-4 alkoxy, aryl XII , or heteroaryl;
R XII-2 is hydrogen or C 1-7 alkyl; or
R XII-1 and R XII-2 together with the nitrogen to which they are attached form morpholine which may be optionally substituted by XII- aryl or C 1-7 alkyl;
W XII is a heterocycle of formula W1 XII , W3 XII , or W4 XII ;
[It is intended that the R 4 and R 8 substituent and substituents A-F, J and K on the W1 XII , W3 XII , and W4 XII Formulae above, as well as the W numbers under the formulas, be succeeded by the Roman Numeral XII.]
A XII is CR XII-4 or nitrogen;
B XII is CR XII-5 or nitrogen;
C XII is C RXII-6 or nitrogen;
E XII and F XII are such that
a) one is oxygen and the other is C(═O); or
b) E XII is C(═O) and F XII is NR XII-7 ;
J XII and K XII are such that
a) J XII is nitrogen and K XII is CR XII-8 ; or
b) J XII is CR XII-6 and K XII is nitrogen;
with the provisos that when W XII is of formula W3 XII and
J XII is nitrogen, then at least one of A XII and B XII is nitrogen;
R XII-4 is H, halogen, or C 1-4 alkyl optionally substituted by one to three halogens;
R XII-5 is
a) H,
b) halo,
c) OR XII-12 ,
d) SR XII-12 ,
e) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XII-12 , SR XII-12 , NR XII-10 R XII-11 , or halo,
f) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XII-12 , SR XII-12 , or NR XII-10 R XII-11 ,
g) (C═O)R XII-9 ,
h) S(O) m XII R XII-9 ,
i) (C═O)OR XII-2 ,
j) NHSO 2 R XII-9 ,
k) nitro, or
l) cyano;
R XII-6 is
a) H,
b) halo,
c) aryl XII ,
d) het XII ,
e) OR XII-12 ,
f) SR XII-2 ,
g) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XII-12 , SR XII-12 , NR XII-10 R XII-11 , aryl XII , halo, C 3-8 cycloalkyl optionally substituted by OR 12 , or het XII , attached through a carbon atom,
h) NR XII-10 R XII-11 ,
i) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XII-12 , SR XII-12 , or NR XII-10 R XII-11 ,
j) (C═O)R XII-9 ,
k) S(O) m XII R XII-9 ,
l) (C═O)OR XII-2 ,
m) NHSO 2 R XII-9 ,
n) nitro, or
o) cyano;
R XII-7 is
a) H,
b) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XII-12 , SR XII-12 , NR XII-10 R XII-11 , or halo,
c) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, XII-12 XII-12 or 10 XI1 OR XII-12 , SR XII-12 , or NR XII-10 R XII-11 ,
d) aryl XII , or
e) het XII ;
R XII-8 is
a) H,
b) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XII-12 , SR XII-12 , NR XII-10 R XII-11 , or halo,
c) OR XII-12 , or
d) SR XII-12 ;
R XII-9 is
a) C 1-7 alkyl,
b) NR XII-10 R XII-11 ,
c) aryl XII , or
d) het XII , wherein said het XII is bound through a carbon atom;
R XII-10 and R XII-11 are independently
a) H,
b) aryl XII ,
c) C 1-7 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from CONR 2 R 2 , CO 2 R 2 , het XII , aryl XII , cyano, or halo,
d) C 2-7 alkyl which may be partially unsaturated and is substituted by one or more substituents selected from NR XII-2 R XII-2 , OR XII-2 , or SR XII-2 ,
e) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XII-2 , SR XII-2 , or NR XII-2 R XII-2 , or
f) R XII-10 and R XII-11 together with the nitrogen to which they are attached form a het XII ;
R XII-12 is
a) H,
b) aryl XII ,
c) het XII ,
d) C 1-7 alkyl optionally substituted by aryl XII , het XII , or halogen,
e) C 2-7 alkyl substituted by OR XII-2 , SR XII-2 , or NR XII-2 R XII-2 , or
f) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XII-2 , SR XII-2 , or NR XII-2 R XII-2 ;
each m XII is independently 1 or 2;
aryl XII is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic, and aryl XII maybe optionally substituted with one or more substituents selected from halo, OH, cyano, NR XII-2 R XII-2 , CO 2 R XII-2 , CF 3 , C 1-6 alkoxy, and C 1-6 alkyl which maybe further substituted by one to three SR XII-2 , NR XII-2 R XII-2 , OR XII-2 , or CO 2 R XII-2 groups;
het XII is a four- (4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from oxygen, sulfur, or nitrogen, which is optionally fused to a benzene ring, or any bicyclic heterocycle group, and het XII may be optionally substituted with one or more substituents selected from halo, OH, cyano, phenyl, CO 2 R XII-2 , CF 3 , C 1-6 alkoxy, oxo, oxime, and C 1-6 alkyl which may be further substituted by one to three SR XII-2 , NR XII-2 R XII-2 , OR XII-2 , or CO 2 R XII-2 groups;
halo or halogen is F, Cl, Br, I;
1 represents the point of attachment between W XII and G XII ;
2 represents the point of attachment between W XII and the carbonyl group of Formula (I);
and a pharmaceutically acceptable salt thereof;
wherein Formula XIII is
wherein,
X XIII is Cl, Br, F, CN or NO 2 ;
G XIII is
a) C 3-7 alkyl which is partially unsaturated and is substituted by hydroxy, or
b) C 1-7 alkyl substituted by NR XIII-1 R XIII-2 or 4-tetrahydropyran;
R XIII-1 is C 2-7 alkyl substituted by hydroxy, C 1-4 alkoxy, aryl XII , or heteroaryl XII ;
R XIII-2 is hydrogen or C 1-7 alkyl; or
R XIII-1 and R XIII-2 together with the nitrogen to which they are attached form morpholine which may be optionally substituted by aryl XII or C 1-7 alkyl;
W XIII is
B XIII is CR XIII-5 , or nitrogen;
C XIII is CR XIII-6 or nitrogen;
with the provisos that B XIII and C XIII cannot be both nitrogen;
R XIII-4 is H, halogen, or C 1-4 alkyl optionally substituted by one to three halogens;
R XIII-5 is
a) H,
b) halo,
c) OR XIII-12 ,
d) SR XIII-12 ,
e) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XIII-12 , SR XIII-12 , NR XIII-10 R XIII-11 , or halo,
f) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XIII-12 , SR XIII-12 , or NR XIII-10 R XIII-11 ,
g) (C═O)R XIII-9 ,
h) S(O) m XIII R XIII-9 ,
i) (C═O)OR XIII-2 ,
j) NHSO 2 R XIII-9 ,
k) nitro, or
l) cyano;
R XIII-6 is
a) H,
b) halo,
c) aryl XIII ,
d) het XIII , or
e) R XIII-7 ;
R XIII-7 is
a) OR XIII-12 ,
b) SR XIII-12 ,
c) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XIII-12 , SR XIII-12 , NR XIII-10 R XIII-11 , aryl XIII , halo, C 3-8 cycloalkyl optionally substituted by OR XIII-12 , or het XIII attached through a carbon atom,
d) NR XIII-10 R XIII-11 ,
e) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XIII-12 , SR XIII-12 , or NR XIII-10 R XIII-11 ,
f) (C═O)R XIII-9 ,
g) S(O) m XIII R XIII-9 ,
h) (C═O)OR XIII-2 ,
i) NHSO 2 R XIII-9 ,
j) nitro, or
k) cyano;
R XIII-8 is
a) H,
b) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XIII-12 , SR XIII-12 , NR XIII-10 R XIII-11 , or halo,
c) OR XIII-12 , or
d) SR XIII-12 ,
R XII-9 is
a) C 1-7 alkyl,
b) NR XIII-10 R XIII-11 ,
c) aryl XIII , or
d) het XIII , wherein said het XIII is bound through a carbon atom;
R XIII-10 and R XIII-11 are independently
a) H,
b) aryl XIII ,
c) C 1-7 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from CONR XIII-2 R XIII-2 , CO 2 R XIII-2 , hetX XIII , aryl XIII , cyano, or halo,
d) C 2-7 alkyl which may be partially unsaturated and is substituted by one or more substituents selected from NR XIII-2 R 2 , OR XIII-2 , or SR XIII-2 ,
e) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XIII-2 , SR XIII-2 , or NR XIII-2 R XIII-2 , or
f) R XIII-10 and R XIII-11 together with the nitrogen to which they are attached form a het XIII ;
R XIII-12 is
a) H,
b) aryl XIII ,
c) het XIII ,
d) C 1-7 alkyl optionally substituted by aryl XIII , het XIII , or halogen,
e) C 2-7 alkyl substituted by OR XIII-2 , SR XIII-2 , or NR XIII-2 R XIII-2 , or
f) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XIII-2 , SR XIII-2 , or NR XIII-2 R XII-2 ;
each m XIII is independently 1 or 2;
aryl XIII is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic, and aryl XIII maybe optionally substituted with one or more substituents selected from halo, OH, cyano, NR XIII-2 R XIII-2 , CO 2 R XIII-2 , CF 3 , C 1-6 alkoxy, and C 1-6 alkyl which maybe further substituted by one to three SR XIII-2 , NR XIII-2 R XIII-2 , OR XIII-2 , or CO 2 R XIII-2 groups;
het XIII is a four- (4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from oxygen, sulfur, or nitrogen, which is optionally fused to a benzene ring, or any bicyclic heterocycle group, and XIII- het may be optionally substituted with one or more substituents selected from halo, OH, cyano, phenyl, CO 2 R XIII-2 , CF 3 , C 1-6 alkoxy, oxo, oxime, and C 1-6 alkyl which may be further substituted by one to three SR XIII-2 , NR XIII-2 R XIII-2 , OR XIII-2 , or CO 2 R XIII-2 groups;
halo or halogen is F, Cl, Br, I;
1 represents the point of attachment between W XIII and G XIII ;
2 represents the point of attachment between W and the carbonyl group of Formula (I);
and a pharmaceutically acceptable salt thereof;
wherein Formula XIV is
wherein,
X XIV is Cl, Br, F, CN, or NO 2 ;
G XIV is
a) C 1-4 alkyl which is fully saturated or partially unsaturated and is substituted by hydroxy, or
b) C 1-4 alkyl substituted by NR XIV-1 R XIV-2 or 4-tetrahydropyran;
R XIV-1 is C 2-7 alkyl substituted by hydroxy, C 1-4 alkoxy, heteroaryl, or aryl XIV ;
R XIV-2 is hydrogen or C 1-7 alkyl; or
R XIV-1 and R XIV-2 together with the nitrogen to which they are attached form morpholine which may be optionally substituted by aryl XIV or C 1-7 alkyl; or pyrrolidine substituted by hydroxy;
W XIV is a heterocycle of formula W1 XIV , W2 XIV , W3 XIV , W4 XIV , W5 XIV , W6 XIV , W7 XIV , W8 XIV , W9 XIV , W10 XIV , W11 XIV , W12 XIV , W13 XIV , W14 XIV , W15 XIV , W16 XIV , W17 XIV , W18 XIV , W19 XIV , W20 XIV , W21 XIV or W22 XIV
[It is intended that the R substituents and substituents A-F, J, K and Y on the W Formulae above, as well as the W number under the formulas, be succeeded by the Roman Numeral XIV.]
A XIV is CRXIV 4 or nitrogen;
B XIV is CRXIV-5 or nitrogen;
C XIV is CRXIV-6 or nitrogen;
D XIV is CRXIV-8 or nitrogen;
E XIV and F are such that one is oxygen and the other is C(═O);
J XIV is NR XIV-7 or oxygen;
K XIV and L are defined such that
a) K XIV is CR XIV-5 and L XIV is CR XIV-6 , or
b) K XIV is absent and L XIV is sulfur;
M XIV is oxygen, sulfur, or S(O) m ;
Y XIV is oxygen or sulfur;
R XIV-4 is H, halogen, or C 1-4 alkyl optionally substituted by one to three halogens;
R XIV-5 is
a) H,
b) halo,
c) OR XIV-12 ,
d) SR XIV-12 ,
e) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XIV-12 , SR XIV-12 , NR XIV-10 R XIV-11 , or halo,
f) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XIV-12 , SR XIV-12 , or NR XIV-10 R XIV-11 ,
g) (C═O)R XIV-9 ,
h) S(O) m XIV R XIV-9 ,
i) (C═O)OR XIV-2 ,
j) NHSO 2 R XIV-9 ,
k) nitro, or
l) cyano;
R XIV-6 is
a) H,
b) halo,
c) aryl XIV ,
d) het XIV ,
e) OR XIV-12 ,
f) SR XIV-12 ,
g) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XIV-12 , SR XIV-12 , NR XIV-10 R XIV-11 , XIV- aryl, halo, C 3-8 cycloalkyl optionally substituted by OR XIV-12 , or XIV- het attached through a carbon atom,
h) NR XIV-10 R XIV-11 ,
i) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XIV- 12, SR XIV- 12, or NR XIV-10 R XIV-11 ,
j) (C═O)R XIV-9 ,
k) S(O) m XIV R XIV-9 ,
l) (C═O)OR XIV-2 ,
m) NHSO 2 R XIV-9 ,
n) nitro, or
o) cyano;
R XIV-7 is
a) H,
b) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XIV-12 , SR XIV-12 , NR XIV-10 R XIV-11 , or halo,
c) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XIV-12 , SR XIV-12 , or NR XIV-10 R XIV-11 ,
d) aryl XIV , or
e) het XIV ;
R XIV-8 is
a) H,
b) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XIV-12 , SR XIV-12 , NR XIV-10 R XIV-11 , or halo,
c) OR XIV-12 , or
d) SR XIV-12 ;
R XIV-9 is
a) C 1-7 alkyl,
b) NR XIV-10 R XIV-11 ,
c) aryl XIV , or
d) het XIV wherein said XIV- het is bound through a carbon atom;
R XIV-10 and R XIV-11 are independently
a) H,
b) aryl XIV ,
c) C 1-7 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from CONR XIV-2 R XIV-2 , CO 2 R XIV-2 , het XIV , aryl XIV , cyano, or halo,
d) C 2-7 alkyl which may be partially unsaturated and is substituted by one or more substituents selected from NR XIV-2 R XIV-2 , OR XIV-2 , or SR XIV-2 ,
e) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XIV-2 , SR XIV-2 , or NR XIV-2 R XIV-2 , or
f) R XIV-10 and R XIV-11 together with the nitrogen to which they are attached form a het XIV ;
R XIV-12 is
a) H,
b) aryl XIV ,
c) het XIV
d) C 1-7 alkyl optionally substituted by aryl XIV , or halogen,
e) C 2-7 alkyl substituted by OR XIv-2 , SR XIV-2 , or NR XIV-2 R XIV-2 , or
f) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XIV-2 , SR XIV-2 , or NR XIV-2 R XIV-2 ;
each m XIV is independently 1 or 2;
aryl XIV is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic, and aryl XIV may be optionally substituted with one or more substituents selected from halo, OH, cyano, NR XIV-2 R XIV-2 , CO 2 R XIV-2 , CF 3 , C 1-6 alkoxy, and C 1-6 alkyl which maybe further substituted by one to three SR 2 , NR XIV-2 R XIV-2 , OR XIV-2 , or CO 2 R XIV-2 groups;
het XIV is a four- (4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from oxygen, sulfur, or nitrogen, which is optionally fused to a benzene ring, or any bicyclic heterocycle group, and het XIV may be optionally substituted with one or more substituents selected from halo, OH, cyano, phenyl, CO 2 R XIV-2 , CF 3 , C 1-6 alkoxy, oxo, oxime, and C 1-6 alkyl which may be further substituted by one to three SR XIV-2 , NR XIV-2 R XIV-2 , OR XIV-2 , or CO 2 R XIV-2 groups;
halo or halogen is F, Cl, Br, I;
1 represents the point of attachment between W and G;
2 represents the point of attachment between W and the carbonyl group of Formula (I);
and a pharmaceutically acceptable salt thereof;
wherein Formula XV is
or a pharmaceutically acceptable salt thereof,
wherein,
X XV is Cl, Br, F, CN or NO 2 ;
G XV is
a) C 1-4 alkyl which is fully saturated or partially unsaturated and is substituted by hydroxy, or
b) C 1-4 alkyl substituted by NR XV-1 R XV-2 or 4-tetrahydropyran;
R XV-1 is C 2-7 alkyl substituted by hydroxy, C 1-4 alkoxy, or aryl;
R XV-2 is hydrogen or C 1-7 alkyl; or
R XV-1 and R XV-2 together with the nitrogen to which they are attached form
a) a morpholine which may be optionally substituted by aryl or C 1-7 alkyl; or
b) a pyrrolidine ring substituted by hydroxy;
W XV is a heterocycle of formula W1 XV , W2 XV , W3 XV , W4 XV , W5 XV , W6 XV , W7 XV or W8 XV
[It is intended that the R substituents and substituents A, B, D, E, J, K and L on the W XV-1 to W XV-8 Formulae above, as well as the W number under the formulas, be succeeded by the Roman Numeral XV.]
A XV is CR XV-4 or nitrogen;
B XV is CR XV-5 or nitrogen;
D XV is
a) —(CR 13 R XV-14 ) a XV , where a XV is 2 or 3
b) —(CR 15 R XV-16 ) 4 —,
c) —Y XV —CR 13 R XV-14 —CR 13 R XV-14 —,
d) —CR 13 R XV-14 —Y XV —CR 13 R XV-14 —,
e) —Y XV —CR 13 R XV-14 —Y XV —,
f) —CR 13 R XV-14 —CR 13 R XV-14 —Y XV —,
g) —Y XV —(CR 13 R XV-16 ) n XV —,
h) —Y XV —CR 15 ═CR 15 —,
i) —CR 15 ═CR 15 —Y XV —,
k) —N═CR 15 —Y XV —,
l) —(CR 15 R XV-16 ) b XV —N═CR 15 —, where b XV is 0 or 1
m) —CR 15 ═N—(CR 15 R XV-16 ) b XV —, where b XV is 0 or 1
n) —N═N—,
o) —N═CR 15 —(CR 15 R 16 ) b XV —, where b XV is 0 or 1
p) —CR 15 ═CR 15 —,
q) —N═N—Y XV ,
r) —Y XV N═N—,
s) —Y XV —N═CR 15 , or
t) —CR 15 R XV-16 —Y XV —CR 15 R XV-16 —CR 15 R XV-16 —;
E XV is CR 8 or nitrogen;
J XV is CR 15 or nitrogen;
K XV is
a) —(CR 15 R XV- 16 ) a XV —, where a XV is 2 or 3, or
b) —CR 15 ═CR 15 —;
L XV is
a) —(CR 15 R XV-16 ) a XV —, where a XV is 2 or 3, or
b) —Y XV —(CR 15 R XV-16 )—(CR 15 R XV-16 )—;
Y XV is oxygen, S(O) m XV , or NR XV-7 ;
with the provisos that:
when W XV is of formula W XV 1;
G XV is C 1-4 alkyl which is fully saturated and is substituted by hydroxy or morpholinyl, in which morpholinyl is attached through nitrogen;
A XV is CR XV-4 ; B XV is CR XV-5 ; and
R XV-8 is hydrogen then at least one of R XV-13 , R XV-14 , or R XV-7 is not hydrogen or C 1-7 alkyl;
when W XV is of formula W XV 1, A XV is CR XV-4 , B XV is CR XV-5 , D XV is —Y XV —CR 13 R XV-14 —CR 13 R XV-14 —, and R XV-8 is hydrogen then yXV is not oxygen;
when W XV is of formula W XV 1, A XV is CR XV-14 , and B XV is CR XV-5 then D XV is not —CR 15 ═CR 15 —;
R XV-4 is H, halogen, or C 1-4 alkyl optionally substituted by one to three halogens;
R XV-5 is
a) H,
b) halo,
c) OR XV-12 ,
d) SR XV-12 ,
e) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XV-12 , SR XV-12 , NR XV-10 R XV-11 , or halo,
f) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XV-12 , SR XV-12 , or NR XV-10 R XV-12 ,
g) (C═O)R XV-9 ,
h) S(O) m XV R XV-9 ,
i) (C═O)OR XV-2 ,
j) NHSO 2 R XV-9 ,
k) nitro, or
l) cyano;
R XV-7 is
a) H,
b) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XV-12 , SR XV-12 , NR XV-10 R XV-11 , or halo,
c) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XV-12 , SR XV-12 , or NR XV-10 R XV-11 ,
d) aryl XV ,
e) het XV ,
f) (C═O)R XV-9 , or
g) S(O) m XV R XV-9 ;
R XV-8 is
a) H,
b) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XV-12 , SR XV-12 , NR XV-10 R XV-11 , or halo,
c) OR XV-12 , or
d) SR XV-12 ;
R XV-9 is
a) C 1-7 alkyl optionally substituted by OR XV-12 or NR XV-2 R XV-2 ,
b) C 3-8 cycloalkyl optionally substituted by OR XV-12 or NR XV-2 R XV-2 ,
c) NR XV-10 R XV-11 ,
d) aryl XV , or
e) het XV , wherein said het XV is bound through a carbon atom;
R XV-10 and R XV-11 are independently
a) H,
b) aryl XV ,
c) C 1-7 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from CONR 2 R XV-2 , CO 2 R XV-2 , het XV , aryl XV , cyano, or halo,
d) C 2-7 alkyl which may be partially unsaturated and is substituted by one or more substituents selected from NR XV-2 R XV-2 , OR XV-2 , or SR XV-2 ,
e) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XV-2 , SR XV-2 , or NR XV-2 R XV-2 , or
f) R XV-10 and R XV-11 together with the nitrogen to which they are attached form a het XV ;
R XV-12 is
a) H,
b) aryl XV ,
c) hetXV,
d) C 1-7 alkyl optionally substituted by arylXV, or halogen,
e) C 2-7 alkyl substituted by OR XV-2 , SR XV-2 , or NR XV-2 R XV-2 , or
f) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XV-2 , SR XV-2 , or NR XV-2 R XV-2 ;
R XV-13 , R XV-14 , R XV-15 , and R XV-16 are independently
a) H
b) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more OR XV-12 , SR XV-12 , NR XV-10 R XV-11 , or halo groups,
c) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XV-12 , SR XV-12 , or NR XV-10 R XV-11 ,
d) aryl XV ,
e) het XV , wherein said het XV is bound through a carbon atom,
f) OR XV-12 ,
g) SR XV-12 ,
h) NR XV-10 R XV-11 ;
i) (C═O)OR XV-2 , or
j) R 13 and R 14 or R 15 and R 16 together with the carbon to which they are attached form (C═O);
each m XV is independently 0, 1 or 2;
each n XV is independently 1 or 3;
aryl XV is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic, and aryl XV may be optionally substituted with one or more substituents selected from halo, OH, cyano, NR XV-2 R XV-2 , CO 2 R XV-2 , CF 3 , C 1-6 alkoxy, and C 1-6 alkyl which maybe further substituted by one to three SR XV-2 , NR XV-2 R XV-2 , OR XV-2 , or CO 2 R XV-2 groups;
het XV is a four- (4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from oxygen, sulfur, or nitrogen, which is optionally fused to a benzene ring, or any bicyclic heterocycle group, and XVhet may be optionally substituted with one or more substituents selected from halo, OH, cyano, phenyl, CO 2 R XV-2 , CF 3 , C 1-6 alkoxy, oxo, oxime, and C 1-6 alkyl which may be further substituted by one to three SR XV-2 , NR XV-2 R XV-2 , OR XV-2 , or CO 2 R XV-2 groups;
halo or halogen is F, Cl, Br, I;
1 represents the point of attachment between W XV and GXV;
2 represents the point of attachment between W XV and the carbonyl group of Formula (I);
and pharmaceutically acceptable salts thereof.
2 . A method of claim 1 , wherein the compound administered has the Formula X
and pharmaceutically acceptable salts thereof; wherein ring A X is a saturated or unsaturated fused double or triple heterocyclic ring having 1, 2, 3 or 4 heteroatoms selected from group consisting of oxygen, sulfur, or nitrogen; and wherein R X and X X are the appropriated substitutents, respectively.
3 . The method of claim 2 , wherein the compound administered is selected from the group consisting of compounds 1 to 16:
4 . A method of claim 1 , wherein the compound administered has the Formula XII
wherein,
X XII is Cl, Br, F, CN or NO 2 ;
G XII is
a) C 1-7 alkyl which partially unsaturated and is substituted by hydroxy, or
b) C 1-4 alkyl substituted by NR XII-1 R XII-2 or 4-tetrahydropyran;
R XII-1 is C 2-7 alkyl substituted by hydroxy, C 1-4 alkoxy, aryl XII , or heteroaryl;
R XII-2 is hydrogen or C 1-7 alkyl; or
R XII-1 and R XII-2 together with the nitrogen to which they are attached form morpholine which may be optionally substituted by XII- aryl or C 1-7 alkyl;
W XII is a heterocycle of formula W1 XII , W3 XII , or W4 XII ;
[It is intended that the R 8 substituents and substituents A-F, J and K on the W1 XII , W3 XII , and W4 XII Formulae above, as well as the W number under the formulas, be succeeded by the Roman Numeral XII.]
A XII is CR XII-4 or nitrogen;
B XII is CR XII-5 or nitrogen;
C XII is CR XII-6 or nitrogen;
E XII and F XII are such that
a) one is oxygen and the other is C(═O); or
b) E XII is C(═O) and F XII is NR XII-7 ;
J XII and K XII are such that
a) J XII is nitrogen and K is CR XII-8 ; or
b) J XII is CR XII-6 and K is nitrogen;
with the provisos that when W XII is of formula W3 XII and J XII is nitrogen, then at least one of A XII and B XII is nitrogen;
R XII-4 is H, halogen, or C 1-4 alkyl optionally substituted by one to three halogens;
R XII-5 is
a) H,
b) halo,
c) OR XII-12 ,
d) SR XII-12 ,
e) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XII-12 , SR XII-12 , NR XII-10 R XII-11 , or halo,
f) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XII-12 , SR XII-12 , or NR XIII-10 R XII-11 ,
g) (C═O)R XII-9 ,
h) S(O) m XII R XII-9 ,
i) (C═O)OR XII-2 ,
j) NHSO 2 R XII-9 ,
k) nitro, or
l) cyano;
R XII-6 is
a) H,
b) halo,
c) aryl XII ,
d) het XII ,
e) OR XII-12 ,
f) SR XII-12 ,
g) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XII-12 , SR XII-12 , NR XII-10 R XII-11 , aryl XII , halo, C 3-8 cycloalkyl optionally substituted by OR 12 , or het XII attached through a carbon atom,
h) NR XII-10 R XII-11 ,
i) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XII-12 , SR XII-12 , or NR XII-10 R XII-11 ,
j) (C═O)R XII-9 ,
k) S(O) m XII R XII-9 ,
l) (C═O)OR XII-2 ,
m) NHSO 2 R XII-9 ,
n) nitro, or
o) cyano;
R XII-7 is
a) H,
b) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XII-12 , SR XII-12 , NR XII-10 R XII-11 , or halo,
c) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XII-12 , SR XII-12 , or NR XII-10 R XII-11 ,
d) aryl XII , or
e) het XII ;
R 8 is
a) H,
b) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XII-12 , SR XII-12 , NR XII-10 R XII-11 , or halo,
c) OR XII-12 , or
d) SR XII-12 ;
R XII-9 is
a) C 1-7 alkyl,
b) NR XII-10 R XII-11 ,
c) aryl XII , or
d) het XII , wherein said het XII is bound through a carbon atom;
R XII-10 and R XII-11 are independently
a) H,
b) aryl XII ,
c) C 1-7 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from CONR 2 R 2 , CO 2 R 2 , het XII , aryl XII , cyano, or halo,
d) C 2-7 alkyl which may be partially unsaturated and is substituted by one or more substituents selected from NR XII-2 R XII-2 , OR XII-2 , or SR XII-2 ,
e) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XII-2 , SR XII-2 , or NR XII-2 R XII-2 , or
f) R XII-10 and R XII-11 together with the nitrogen to which they are attached form a het XII ;
R XII-12 is
a) H,
b) aryl XII ,
c) het XII ,
d) C 1-7 alkyl optionally substituted by aryl XII , het XII , or halogen,
e) C 2-7 alkyl substituted by OR XII-2 , SR XII-2 , or NR XII-2 R XII-2 , or
f) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XII-2 , SR XII-2 , or NR XII-2 R XII-2 ;
each m XII is independently 1 or 2;
aryl XII is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic, and aryl XII maybe optionally substituted with one or more substituents selected from halo, OH, cyano, NR XII-2 R XII-2 , CO 2 R XII-2 , CF 3 , C 1-6 alkoxy, and C 1-6 alkyl which maybe further substituted by one to three SR XII-2 NR XII-2 R XII-2 , OR XII-2 , or CO 2 R XII-2 groups;
het XII is a four- (4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from oxygen, sulfur, or nitrogen, which is optionally fused to a benzene ring, or any bicyclic heterocycle group, and het XII may be optionally substituted with one or more substituents selected from halo, OH, cyano, phenyl, CO 2 R XII-2 , CF 3 , C 1-6 alkoxy, oxo, oxime, and C 1-6 alkyl which may be further substituted by one to three SR XII-2 , NR XII-2 R XII-2 , OR XII-2 , or CO 2 R XII-2 groups;
halo or halogen is F, Cl, Br, I;
1 represents the point of attachment between W XII and G XII ;
2 represents the point of attachment between W XII and the carbonyl group of Formula (I);
and a pharmaceutically acceptable salt thereof.
5 . The method according to claim 4 , wherein the compound administered is:
(1) N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-2-oxo-2H-pyrano[2,3-c]pyridine-3-carboxamide; (2) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-1-oxo-1H-isochromene-3-carboxamide; (3) N-(4-chlorobenzyl)-4-hydroxy-1-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1H-isochromene-3-carboxamide; (4) N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-1-oxo-1H-isochromene-3-carboxamide; (5) N-(4-chlorobenzyl)-5-hydroxy-3-(3-hydroxy-1-propynyl)-8-oxo-7,8-dihydro[1,7]naphthyridine-6-carboxamide; (6) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxamide; (7) N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxamide; (8) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)[1,7]naphthyridine-3-carboxamide; (9) N-(4-chlorobenzyl)-8-ethoxy-4-hydroxy-6-(3-hydroxy-1-propynyl)[1,7]naphthyridine-3-carboxamide; (10) N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)[1,7]naphthyridine-3-carboxamide; (11) N-(4-chlorobenzyl)-8-ethoxy-4-hydroxy-6-(4-morpholinylmethyl)[1,7]naphthyridine-3-carboxamide; (12) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)[1,5]naphthyridine-3-carboxamide; (13) N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)[1,5]naphthyridine-3-carboxamide; (14) N-(4-chlorobenzyl)-4-hydroxy-6-(tetrahydro-2H-pyran-4-ylmethyl)[1,5]naphthyridine-3-carboxamide; (15) N-(4-chlorobenzyl)-8-hydroxy-2-(3-hydroxy-1-propynyl)pyrido[3,2-d]pyrimidine-7-carboxamide; (16) N-(4-chlorobenzyl)-8-hydroxy-2-(4-morpholinylmethyl)pyrido[3,2-d]pyrimidine-7-carboxamide; (17) N-(4-chlorobenzyl)-5-hydroxy-3-(4-morpholinylmethyl)[1,7]naphthyridine-6-carboxamide; (18) N-(4-chlorobenzyl)-5-hydroxy-3-(3-hydroxy-1-propynyl)[1,7]naphthyridine-6-carboxamide; (19) N-(4-chlorobenzyl)-5-hydroxy-3-(tetrahydro-2H-pyran-4-ylmethyl)[1,7]naphthyridine-6-carboxamide; (20) N-(4-chlorobenzyl)-4-hydroxy-6-(4-morpholinylmethyl)-3-isoquinolinecarboxamide; (21) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-isoquinolinecarboxamide; (22) N-(4-chlorobenzyl)-4-hydroxy-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-isoquinolinecarboxamide; or a pharmaceutically acceptable salt thereof.
6 . The method of claim 1 , wherein the compound administered has the Formula XIII
wherein,
X XIII is Cl, Br, F, CN or NO 2 ;
G XIII is
a) C 3-7 alkyl which is partially unsaturated and is substituted by hydroxy, or
b) C 1-7 alkyl substituted by NR XIII-1 R 2 or 4-tetrahydropyran;
R XIII-1 is C 2-7 alkyl substituted by hydroxy, C 1-4 alkoxy, aryl XIII , or heteroaryl;
R XIII-2 is hydrogen or C 1-7 alkyl; or
R XIII-1 and R XIII-2 together with the nitrogen to which they are attached form morpholine which may be optionally substituted by aryl or C 1-7 alkyl;
W XIII is
B XIII is C RXIII-5 or nitrogen;
C XIII is C RXIII-6 or nitrogen;
with the provisos that B XIII and C XIII cannot be both nitrogen;
R XIII-4 is H, halogen, or C 1-4 alkyl optionally substituted by one to three halogens;
R XIII-5 is
a) H,
b) halo,
c)OR XIII-12 ,
d) SR XIII-12 ,
e) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XIII-12 , SR XIII-12 , NR XIII-10 R XIII-11 , or halo,
f) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XIII-12 , SR XIII-2 , or NR XIII-10 R XIII-11 ,
g) (C═O)R XIII-9 ,
h) S(O) m XIII R XIII-9 ,
i) (C═O)OR XIII-2 ,
j) NHSO 2 R XIII-9 ,
k) nitro, or
l) cyano;
R XIII-6 is
a) H,
b) halo,
c) aryl XIII ,
d) het XIII , or
e) R XIII-7 ;
R XIII-7 is
a) OR XIII-12 ,
b) SR XIII-12 ,
c) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XIII-12 , SR XIII-12 , NR XIII-10 R XIII-11 , aryl XIII , halo, C 3-8 cycloalkyl optionally substituted by OR XIII-12 , or het XIII attached through a carbon atom,
d) NR XIII-10 R XIII-11 ,
e) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XIII-12 , SR XIII-12 , or NR XIII-10 R XIII-11 ,
f) (C═O)R XIII-9 ,
g) S(O) m XIII R XIII-9 ,
h) (C═O)OR XIII-2 ,
i) NHSO 2 R XIII-9 ,
j) nitro, or
k) cyano;
R XIII-8 is
a) H,
b) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XIII-12 , SR XIII-12 , NR XIII-10 R XIII-11 , or halo,
c) OR XII-12 , or
d) SR XIII-12 ;
R XIII-9 is
a) C 1-7 alkyl,
b) NR XIII-10 R XIII-11 ,
c) aryl XIII , or
d) het XIII , wherein said het XIII is bound through a carbon atom;
R XIII-10 and R XIII-11 are independently
a) H,
b) aryl XIII ,
c) C 1-7 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from CONR XIII-2 R XIII-2 , CO 2 R XIII-2 , het XIII , aryl XIII , cyano, or halo,
d) C 2-7 alkyl which may be partially unsaturated and is substituted by one or more substituents selected from NR XIII-2 R XIII-2 , OR XIII-2 , or SR XIII-2 ,
e) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XIII-2 , SR XIII-2 , or NR XIII-2 R XIII-2 , or
f) R XIII-10 and R XIII-11 together with the nitrogen to which they are attached form a het XIII ;
R XIII-12 is
a) H,
b) aryl XIII ,
c) het XIII ,
d) C 1-7 alkyl optionally substituted by aryl XIII , het XIII , or halogen,
e) C 2-7 alkyl substituted by OR XIII-2 , SR XIII-2 , or NR XIII-2 R XIII-2 , or
f) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XIII-2 , SR XIII-2 , or NR XIII-2 R XIII-2 ;
each m XIII is independently 1 or 2;
aryl XIII is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic, and aryl XII maybe optionally substituted with one or more substituents selected from halo, OH, cyano, NR XIII-2 R XIII-2 , CO 2 R XIII-2 , CF 3 , C 1-6 alkoxy, and C 1-6 alkyl which maybe further substituted by one to three SR XIII-2 , NR XIII-2 R XIII-2 , OR XIII-2 , or CO 2 R XIII-2 groups;
het XIII is a four- (4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from oxygen, sulfur, or nitrogen, which is optionally fused to a benzene ring, or any bicyclic heterocycle group, and het XIII may be optionally substituted with one or more substituents selected from halo, OH, cyano, phenyl, CO 2 R XIII-2 , CF 3 , C 1-6 alkoxy, oxo, oxime, and C 1-6 alkyl which may be further substituted by one to three SR XIII-2 , NR XIII-2 R XIII-2 , OR XIII-2 , or CO 2 R XIII-2 groups;
halo or halogen is F, Cl, Br, I;
1 represents the point of attachment between W XIII and G XIII ;
2 represents the point of attachment between W XIII and the carbonyl group of Formula (XIV);
and a pharmaceutically acceptable salt thereof.
7 . The method of claim 6 , wherein W XIII-2 is of the formula W2.1, as set forth on page 10 of the specification of application Ser. No. 09/887,226 filed Jun. 22, 2001.
8 . The method of claim 6 , wherein W XIII-2 is of the formula W2.2, as set forth on page 10 of the specification of application Ser. No. 09/887,226, filed Jun. 22, 2001.
9 . The method of claim 6 , wherein the compound administered is selected from the group consisting of
(1) N-(4-chlorobenzyl)-5-hydroxy-3-(4-morpholinylmethyl)-6-isoquinolinecarboxamide; (2) N-(4-chlorobenzyl)-5-hydroxy-3-(tetrahydro-2H-pyran-4-ylmethyl)-6-isoquinolinecarboxamide; (3) N-(4-chlorobenzyl)-5-hydroxy-3-(3-hydroxy-1-propynyl)-6-isoquinolinecarboxamide; (4) N-(4-chlorobenzyl)-5-hydroxy-3-(4-morpholinylmethyl)-6-quinolinecarboxamide; or a pharmaceutically acceptable salt thereof.
10 . The method of claim 1 , wherein the compound administered has the Formula XIV
wherein,
X XIV is Cl, Br, F, CN, or NO 2 ;
G XIV is
a) C 1-4 alkyl which is fully saturated or partially unsaturated and is substituted by hydroxy, or
b) C 1-4 alkyl substituted by NR XIV-1 R XIV-2 or 4-tetrahydropyran;
R XIV-1 is C 2-7 alkyl substituted by hydroxy, C 1-4 alkoxy, heteroaryl, or aryl XIV ;
R XIV-2 is hydrogen or C 1-7 alkyl; or
R XIV-1 and R XIV-2 together with the nitrogen to which they are attached form morpholine which may be optionally substituted by aryl XIV or C 1-7 alkyl; or pyrrolidine substituted by hydroxy;
W XIV is a heterocycle of formula W1 XIV , W2 XIV , W3 XIV , W4 XIV , W5 XIV , W6 XIV , W7 XIV , W8 XIV , W9 XIV , W10 XIV , W11 XIV , W12 XIV , W13 XIV , W14 XIV , W15 XIV , W16 XIV , W17 XIV , W18 XIV , W19 XIV , W20 XIV , W21 XIV or W22 XIV
[It is intended that the R substituents and substituents A-F, J, K, L, M and Y on the W Formulae above, as well as the W number under the formulas, be succeeded by the Roman Numeral XIV.]
A XIV is CR XV-4 or nitrogen;
B XIV is CR XV-5 or nitrogen;
C XIV is CR XV-6 or nitrogen;
D XIV is CR XV-8 or nitrogen;
E XIV and F are such that one is oxygen and the other is C(═O);
J XIV is NR XV-7 or oxygen;
K XIV and L XIV are defined such that
a) K XIV is CR XIV-5 and L XIV is CR XV-6 , or
b) K XIV is absent and L XIV is sulfur;
M XIV is oxygen, sulfur, or S(O) m ;
Y XIV is oxygen or sulfur;
The suffixed numbered “R” groups in the definitions thereof correspond to the numbered groups of Formulas W1-W22.
R XIV-4 is H, halogen, or C 1-4 alkyl optionally substituted by one to three halogens;
R XIV-5 is
a) H,
b) halo,
c) OR XIV-12 ,
d) SR XIV-12 ,
e) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XIV-12 , SR XIV-12 , NR XIV-10 R XIV-11 , or halo,
f) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR 1XIV-2 , SR XIV-12 , or NR XIV-10 R XIV-11 ,
g) (C═O)R XIV-9 ,
h) S(O) m XIV R XIV-9 ,
i) (C═O)OR XIV-2 ,
j) NHSO 2 R XIV-9 ,
k) nitro, or
l) cyano;
R XIV-6 is
a) H,
b) halo,
c) aryl XIV ,
d) het XIV ,
e) OR XIV-12 ,
f) SR XIV-12 ,
g) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XIV-12 , SR XIV-12 , NR XIV-10 R XIV-11 , aryl XIV , halo, C 3-8 cycloalkyl optionally substituted by OR XIV-12 , or het XIV attached through a carbon atom,
h) NR XIV-10 R XIV-11 ,
i) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XIV-12 , SR XIV-12 , or NR XIV-10 R XIV-11 ,
j) (C═O)R XIV-9 ,
k) S(O) m XIV R XIV-9 ,
l) (C═O)OR XIV-2 ,
m) NHSO 2 R XIV-9 ,
n) nitro, or
o) cyano;
R XV-7 is
a) H,
b) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XIV-12 , SR XIV-12 , NR XIV-10 R XIV-11 , or halo,
c) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XIV-12 , SR XIV-12 , or NR XIV-10 R XIV-11 ,
d) aryl XIV , or
e) het XIV ;
R XIV-8 is
a) H,
b) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XIV-12 , SR XIV-12 , NR XIV-10 R XIV-11 , or halo,
c) OR XIV-12 , or
d) SR XIV-12 ;
R XIV-9 is
a) C 1-7 alkyl,
b) NR XIV-10 R XIV-11 ,
c) aryl XIV , or
d) het XIV , wherein said hetXV is bound through a carbon atom;
R XIV-10 and R XIV-11 are independently
a) H,
b) aryl XIV ,
c) C 1-7 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from CONR XIV-2 R XIV-2 , CO 2 R XIV-2 , het XIV , aryl XIV , cyano, or halo,
d) C 2-7 alkyl which may be partially unsaturated and is substituted by one or more substituents selected from NR XIV-2 R XIV-2 , OR XIV-2 , or SR XIV-2 ,
e) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XIV-2 , SR XIV-2 , or NR XIV-2 R XIV-2 , or
f) R XIV-10 and R XIV-11 together with the nitrogen to which they are attached form a het XIV ;
R XIV-12 is
a) H,
b) aryl XIV ,
c) het XIV ,
d) C 1-7 alkyl optionally substituted by aryl XIV , or halogen,
e) C 2-7 alkyl substituted by OR XIV-2 , SR XIV-2 , or NR XIV-2 R XIV-2 , or
f) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XIV-2 , SR XIV-2 , or NR XIV-2 R XIV-2 ;
each m XIV is independently 1 or 2;
aryl XIV is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic, and aryl XIV may be optionally substituted with one or more substituents selected from halo, OH, cyano, NR XIV-2 R XIV-2 , CO 2 R XIV-2 , CF 3 , C 1-6 alkoxy, and C 1-6 alkyl which maybe further substituted by one to three SR XIV-2 , NR XIV-2 R XIV-2 , OR XIV-2 , or CO 2 R XIV-2 , groups;
het XIV is a four- (4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from oxygen, sulfur, or nitrogen, which is optionally fused to a benzene ring, or any bicyclic heterocycle group, and het XIV may be optionally substituted with one or more substituents selected from halo, OH, cyano, phenyl, CO 2 R XIV-2 , CF 3 , C 1-6 alkoxy, oxo, oxime, and C 1-6 alkyl which may be further substituted by one to three SR XIV-2 , NR XIV-2 R XIV-2 , OR XIV-2 , or CO 2 R XIV-2 groups;
halo or halogen is F, Cl, Br, I;
1 represents the point of attachment between W XIV and G XIV ;
2 represents the point of attachment between W XIV and the carbonyl group of Formula (I);
or a pharmaceutically acceptable salt thereof.
11 . The method according to claim 10 , wherein the compound administered is:
(1) N-(4-chlorobenzyl)-5-hydroxy-3-(3-hydroxy-1-propynyl)-2-oxo-2H-chromene-6-carboxamide; (2) N-(4-chlorobenzyl)-5-hydroxy-3-(3-hydroxypropyl)-2-oxo-2H-chromene-6-carboxamide; (3) N-(4-chlorobenzyl)-5-hydroxy-3-(4-morpholinylmethyl)-2-oxo-2H-chromene-6-carboxamide; (4) N-(4-chlorobenzyl)-5-hydroxy-4-methyl-3,8-bis(4-morpholinylmethyl)-2-oxo-2H-chromene-6-carboxamide; (5) N-(4-chlorobenzyl)-5-hydroxy-3-(3-hydroxy-1-propynyl)-1-methyl-2-oxo-1,2-dihydro-6-quinolinecarboxamide; (6) N-(4-chlorobenzyl)-5-hydroxy-3-(3-hydroxypropyl)-1-methyl-2-oxo-1,2-dihydro-6-quinolinecarboxamide; (7) N-(4-chlorobenzyl)-5-hydroxy-1-methyl-3-(4-morpholinylmethyl)-2-oxo-1,2-dihydro-6-quinolinecarboxamide; (8) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro[1,7]naphthyridine-3-carboxamide; (9) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1-methyl-4-oxo-1,4-dihydro[1,7]naphthyridine-3-carboxamide; (10) N-(4-chlorobenzyl)-1-methyl-6,8-bis(morpholin-4-ylmethyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxamide; (11) N-(4-chlorobenzyl)-8-ethoxy-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro[1,7]naphthyridine-3-carboxamide; (12) N-(4-chlorobenzyl)-8-ethoxy-6-(3-hydroxypropyl)-1-methyl-4-oxo-1,4-dihydro[1,7]naphthyridine-3-carboxamide; (13) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro[1,7]naphthyridine-3-carboxamide; (14) 8-chloro-N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro1,7]naphthyridine-3-carboxamide; (15) N-(4-chlorobenzyl)-8-ethoxy-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro[1,7]naphthyridine-3-carboxamide; (16) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1-methyl-4-oxo-1,4-dihydro[1,5]naphthyridine-3-carboxamide; (17) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro[1,5]naphthyridine-3-carboxamide; (18) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro[1,5]naphthyridine-3-carboxamide; (19) N-(4-chlorobenzyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro[1,5]naphthyridine-3-carboxamide; (20) N-(4-chlorobenzyl)-8-ethyl-3-(4-morpholinylmethyl)-5-oxo-5,8-dihydropyrido[2,3-c]pyridazine-6-carboxamide; (21) N-(4-chlorobenzyl)-2-(3-hydroxypropyl)-5-methyl-8-oxo-5,8-dihydropyrido[3,2-d]pyrimidine-7-carboxamide; (22) N-(4-chlorobenzyl)-2-(3-hydroxy-1-propynyl)-5-methyl-8-oxo-5,8-dihydropyrido[3,2-d]pyrimidine-7-carboxamide; (23) N-(4-chlorobenzyl)-5-methyl-2-(4-morpholinylmethyl)-8-oxo-5,8-dihydropyrido[3,2-d]pyrimidine-7-carboxamide; (24) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxamide; (25) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1-methyl-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxamide; (26) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxamide; (27) N-(4-chlorobenzyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxamide; (28) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo-1,4-dihydropyrido[3,4-c]pyridazine-3-carboxamide; (29) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-1,4-dihydropyrido[3,4-c]pyridazine-3-carboxamide; (30) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1-methyl-4-oxo-1,4-dihydropyrido[3,4-c]pyridazine-3-carboxamide; (31) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydropyrido[3,4-c]pyridazine-3-carboxamide; (32) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydropyrido[3,4-c]pyridazine-3-carboxamide; (33) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydropyrido[3,4-c]pyridazine-3-carboxamide; (34) N-(4-chlorobenzyl)-7-(3-hydroxy-1-propynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide; (35) N-(4-chlorobenzyl)-7-(3-hydroxypropyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide; (36) N-(4-chlorobenzyl)-7-(4-morpholinylmethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide; (37) N-(4-chlorobenzyl)-4-hydroxy-7-(3-hydroxy-1-propynyl)-2-oxo-2H-pyrido[1,2-a]pyrimidine-3-carboxamide; (38) N-(4-chlorobenzyl)-2-hydroxy-7-(3-hydroxypropyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide; (39) N-(4-chlorobenzyl)-7-(3-hydroxypropyl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-3-carboxamide; (40) N-(4-chlorobenzyl)-7-(3-hydroxy-1-propynyl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-3-carboxamide; (41) N-(4-chlorobenzyl)-7-(4-morpholinylmethyl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-3-carboxamide; (42) N-(4-chlorobenzyl)-7-(3-hydroxy-1-propynyl)-4-oxo-4H-pyrimido[1,2-b]pyridazine-3-carboxamide; (43) N-(4-chlorobenzyl)-7-(3-hydroxypropyl)-4-oxo-4H-pyrimido[1,2-b]pyridazine-3-carboxamide; (44) N-(4-chlorobenzyl)-4-oxo-7-(tetrahydro-2H-pyran-4-ylmethyl)-4H-pyrimido[1,2-b]pyridazine-3-carboxamide; (45) N-(4-chlorobenzyl)-7-(4-morpholinylmethyl)-4-oxo-4H-pyrimido[1,2-b]pyridazine-3-carboxamide; (46) N-(4-chlorobenzyl)-7-(3-hydroxypropyl)-4-oxo-4H-pyrimido[1,2-a]pyrimidine-3-carboxamide; (47) N-(4-chlorobenzyl)-7-(3-hydroxy-1-propynyl)-4-oxo-4H-pyrimido[1,2-a]pyrimidine-3-carboxamide; (48) N-(4-chlorobenzyl)-4-oxo-7-(tetrahydro-2H-pyran-4-ylmethyl)-4H-pyrimido[1,2-a]pyrimidine-3-carboxamide; (49) N-(4-chlorobenzyl)-7-(4-morpholinylmethyl)-4-oxo-4H-pyrimido[1,2-a]pyrimidine-3-carboxamide; (50) N-(4-chlorobenzyl)-2-(3-hydroxypropyl)-8-oxo-8H-pyrimido[1,2-b][1,2,4]triazine-7-carboxamide; (51) NA-(4-chlorobenzyl)-2-(3-hydroxy-1-propynyl)-8-oxo-8H-pyrimido[1,2-b][1,2,4]triazine-7-carboxamide; (52) N-(4-chlorobenzyl)-7-(4-morpholinylmethyl)-4-oxo-4H-quinolizine-3-carboxamide; (53) N-(4-chlorobenzyl)-7-(3-hydroxypropyl)-4-oxo-4H-quinolizine-3-carboxamide; (54) N-(4-chlorobenzyl)-7-(3-hydroxy-1-propynyl)-4-oxo-4H-quinolizine-3-carboxamide; (55) N-(4-chlorobenzyl)-7-(3-hydroxy-1-propynyl)-4-oxo-4H-pyrido[1,2-a]pyrazine-3-carboxamide; (56) N-(4-chlorobenzyl)-7-(3-hydroxypropyl)-4-oxo-4H-pyrido[1,2-a]pyrazine-3-carboxamide; (57) N-(4-chlorobenzyl)-7-(4-morpholinylmethyl)-4-oxo-4H-pyrido[1,2-a]pyrazine-3-carboxamide; (58) N-(4-chlorobenzyl)-3-(4-morpholinylmethyl)-6-oxo-6H-pyrido[1,2-a]pyrimidine-7-carboxamide; (59) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-4H-chromene-3-carboxamide; (60) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-4H-chromene-3-carboxamide; (61) N-(4-chlorobenzyl)-6-(((3R)-3-hydroxypyrrolidinyl)methyl)-4-oxo-4H-chromene-3-carboxamide; (62) N-(4-chlorobenzyl)-6,8-bis(4-morpholinylmethyl)-4-oxo-4H-chromene-3-carboxamide; (63) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo-4H-chromene-3-carboxamide; (64) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo-4H-pyrano[2,3-b]pyridine-3-carboxamide; (65) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-4H-pyrano[2,3-b]pyridine-3-carboxamide; (66) N-(4-chlorobenzyl)-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-4H-pyrano[2,3-b]pyridine-3-carboxamide; (67) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-4H-pyrano[2,3-b]pyridine-3-carboxamide; (68) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-4H-thiochromene-3-carboxamide; (69) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo-4H-thiopyrano[2,3-b]pyridine-3-carboxamide; (70) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-4H-thiopyrano[2,3-b]pyridine-3-carboxamide; (71) N-(4-chlorobenzyl)-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-4H-thiopyrano[2,3-b]pyridine-3-carboxamide; (72) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-4H-thiopyrano[2,3-b]pyridine-3-carboxamide; (73) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-4H-1,2-benzoxazine-3-carboxamide; (74) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo-4H-1,2-benzoxazine-3-carboxamide; (75) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-4H-1,2-benzoxazine-3-carboxamide; (76) N-(4-chlorobenzyl)-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-4H-1,2-benzoxazine-3-carboxamide; (77) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-4H-1,2-benzthiazine-3-carboxamide; (78) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-4-oxo-4H-1,2-benzthiazine-3-carboxamide; (79) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-4H-1,2-benzthiazine-3-carboxamide; (80) N-(4-chlorobenzyl)-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-4H-1,2-benzthiazine-3-carboxamide; (81) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-1-methyl-1H-2,1-benzothiazine-3-carboxamide 2,2-dioxide; (82) N-(4-chlorobenzyl)-4-hydroxy-1-methyl-6-(4-morpholinylmethyl)-1H-2,1-benzothiazine-3-carboxamide 2,2-dioxide; (83) N-(4-chlorobenzyl)-4-methyl-7-(4-morpholinylmethyl)-4H-1,4-benzothiazine-2-carboxamide 1-oxide; (84) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-1H-4,1,2-benzothiadiazine-3-carboxamide 4,4-Dioxide; (85) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-1H-thieno[2,3-e][1,3,4]thiadiazine-3-carboxamide 4,4-dioxide; (86) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-1H-thieno[2,3-e][1,3,4]thiadiazine-3-carboxamide 4,4-dioxide; (87) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1H-thieno[2,3-e][1,3,4]thiadiazine-3-carboxamide 4,4-dioxide; (88) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1H-thieno[2,3-e][1,3,4]thiadiazine-3-carboxamide 4,4-dioxide; (89) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1-methyl-1H-thieno[2,3-e][1,3,4]thiadiazine-3-carboxamide 4,4-dioxide; (90) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-1H-thieno[2,3-e][1,3,4]thiadiazine-3-carboxamide 4,4-dioxide; (91) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1,8-dimethyl-4,7-dioxo-1,4,7,8-tetrahydro [1,8]naphthyridine-3-carboxamide; (92) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1,8-dimethyl-4,7-dioxo-1,4,7,8-tetrahydro[1,8]naphthyridine-3-carboxamide; (93) N-(4-chlorobenzyl)-1,8-dimethyl-6-(4-morpholinylmethyl)-4,7-dioxo-1,4,7,8-tetrahydro[1,8]naphthyridine-3-carboxamide; (94) N-(4-chlorobenzyl)-7-(3-hydroxy-1-propynyl)-4-oxo-4H-pyrido[2,1-c][1,2,4]triazine-3-carboxamide; (95) N-(4-chlorobenzyl)-7-(3-hydroxypropyl)-4-oxo-4H-pyrido[2,1-c][1,2,4]triazine-3-carboxamide; (96) N-(4-chlorobenzyl)-7-(4-morpholinylmethyl)-4-oxo-4H-pyrido[2,1-c][1,2,4]triazine-3-carboxamide; (97) N-(4-chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)-1-benzothiophene-5-carboxamide; (98) N-(4-chlorobenzyl)-4-hydroxy-2-(3-hydroxypropyl)-1-benzothiophene-5-carboxamide; (99) N-(4-chlorobenzyl)-2-(4-morpholinylmethyl)-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxamide; (100) N-(4-chlorobenzyl)-5-hydroxy-2-(4-morpholinylmethyl)-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxamide; (101) N-(4-chlorobenzyl)-4-methyl-2-(4-morpholinylmethyl)-7-oxo-4,7-dihydro[1,3]thiazolo[5,4-b]pyridine-6-carboxamide; (102) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydrothieno[2,3-c]pyridazine-3-carboxamide; (103) N-(4-chlorobenzyl)-6-(3-hydroxypropyl)-1-methyl-4-oxo-1,4-dihydrothieno[2,3-c]pyridazine-3-carboxamide; (104) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydrothieno[2,3-c]pyridazine-3-carboxamide; (105) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-phenyl-1,4-dihydrothieno[2,3-c]pyridazine-3-carboxamide; (106) N-(4-chlorobenzyl)-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydrothieno[2,3-c]pyridazine-3-carboxamide; (107) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxyprop-1-ynyl)-1-methyl-1H-thieno[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide; or a pharmaceutically acceptable salt thereof.
12 . The method according to claim 10 , wherein the compound administered is:
(1) N-(4-chlorobenzyl)-7-(3-hydroxy-1-propynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxamide; (2) N-(4-chlorobenzyl)-5-hydroxy-2-(4-morpholinylmethyl)-7-oxo-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidine-6-carboxamide; (3) N-(4-chlorobenzyl)-4-hydroxy-7-(3-hydroxy-1-propynyl)-2-oxo-2H-pyrido[1,2-a]pyrimidine-3-carboxamide; (4) N-(4-chlorobenzyl)-2-(4-morpholinylmethyl)-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxamide; (5) N-(4-chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)-1-benzothiophene-5-carboxamide; (6) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-4H-chromene-3-carboxamide; (7) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-4H-1,2-benzoxazine-3-carboxamide; (8) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxamide; (9) N-(4-chlorobenzyl)-4-methyl-2-(4-morpholinylmethyl)-7-oxo-4,7-dihydro[1,3]thiazolo[5,4-b]pyridine-6-carboxamide; (10) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxyprop-1-ynyl)-1-methyl-1H-thieno[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide; (11) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-1H-4,1,2-benzothiadiazine-3-carboxamide 4,4-Dioxide; (12) 8-chloro-N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro1,7]naphthyridine-3-carboxamide; (13) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro[1,7]naphthyridine-3-carboxamide; (14) N-(4-chlorobenzyl)-1-methyl-6,8-bis(morpholin-4-ylmethyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxamide; (15) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-1-methyl-1H-2,1-benzothiazine-3-carboxamide 2,2-dioxide; (16) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-1H-thieno[2,3-e][1,3,4]thiadiazine-3-carboxamide 4,4-dioxide; (17) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro[1,5]naphthyridine-3-carboxamide; (18) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-1-phenyl-1,4-dihydrothieno[2,3-c]pyridazine-3-carboxamide; (19) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-4H-chromene-3-carboxamide; (20) N-(4-chlorobenzyl)-6,8-bis(4-morpholinylmethyl)-4-oxo-4H-chromene-3-carboxamide; (21) N-(4-chlorobenzyl)-6-(((3R)-3-hydroxypyrrolidinyl)methyl)-4-oxo-4H-chromene-3-carboxamide; or a pharmaceutically acceptable salt thereof.
13 . The method according to claim 10 , wherein the compound administered is:
(1) N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-1H-4,1,2-benzothiadiazine-3-carboxamide 4,4-Dioxide; (2) N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-1-methyl-1H-2,1-benzothiazine-3-carboxamide 2,2-dioxide; (3) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-1H-thieno[2,3-e][1,3,4]thiadiazine-3-carboxamide 4,4-dioxide; (4) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro[1,5]naphthyridine-3-carboxamide; or a pharmaceutically acceptable salt thereof.
14 . The method according to claim 10 , wherein the compound administered is:
(1) N-(4-chlorobenzyl)-4-hydroxy-7-(3-hydroxy-1-propynyl)-2-oxo-2H-pyrido[1,2-a]pyrimidine-3-carboxamide; (2) N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-4-oxo-4H-chromene-3-carboxamide; (3) 8-chloro-N-(4-chlorobenzyl)-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro1,7]naphthyridine-3-carboxamide; (4) N-(4-chlorobenzyl)-1-methyl-6,8-bis(morpholin-4-ylmethyl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxamide; (5) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-4-oxo-4H-chromene-3-carboxamide; (6) N-(4-chlorobenzyl)-6,8-bis(4-morpholinylmethyl)-4-oxo-4H-chromene-3-carboxamide; (7) N-(4-chlorobenzyl)-6-(((3R)-3-hydroxypyrrolidinyl)methyl)-4-oxo-4H-chromene-3-carboxamide; or a pharmaceutically acceptable salt thereof.
15 . The method according to claim 1 , wherein the compound administered has the Formula XV
or a pharmaceutically acceptable salt thereof,
wherein,
X XV is Cl, Br, F, CN or NO 2 ;
G XV is
a) C 1-4 alkyl which is fully saturated or partially unsaturated and is substituted by hydroxy, or
b) C 1-4 alkyl substituted by NR XV-1 R XV-2 or 4-tetrahydropyran;
R XV-1 is C 2-7 alkyl substituted by hydroxy, C 1-4 alkoxy, or aryl;
R XV-2 is hydrogen or C 1-7 alkyl; or
R XV-1 and R XV-2 together with the nitrogen to which they are attached form
a) a morpholine which may be optionally substituted by aryl XV or C 1-7 alkyl; or
b) a pyrrolidine ring substituted by hydroxy;
W XV is a heterocycle of formula W1 XV , W2 XV , W3 XV , W4 XV , W5 XV , W6 XV , W7 XV or W8 XV
[It is intended that the R substituents and substitutents A, B, D, E, J, K and L on the W XV-1 to W XV-8 Formulae, as well as the W number under the formulas, be succeeded by the Roman Numeral XV.]
A XV is CR XV-4 or nitrogen;
B XV is CR XV-5 or nitrogen;
D XV is
a) —(CR XV-13 R XV-14 ) a XV —, where a XV is 2 or 3
b) —(CR XV-15 R XV-16 ) 4 —,
c) —Y XV —CR XV-13 R XV-14 —CR XV-13 R XV-14 —,
d) —CR XV-13 R XV-14 —Y XV —CR XV-13 R XV-14 —,
e) —Y XV —CR XV-13 R XV-14 —Y XV —,
f) —CR XV-13 R XV-14 —CR XV-13 R XV-14 —Y XV —,
g) —Y XV —(CR XV-15 R XV-16 ) n XV —,
h) —Y XV —CR XV-15 ═CR XV-15 —,
i) —Y XV —CR XV-15 ═N—,
j) —CR XV-15 ═CR XV-15 —Y XV —,
k) —N═CR XV-15 —Y XV —,
l) —(CR XV-15 R XV-16 ) b XV —N═CR XV-15 —, where b XV is 0 or 1
m) —CR XV-15 ═N—(CR XV-15 R XV-16 ) b XV —, where b XV is 0 or 1
n) —N═N—,
o) —N═CR XV-15 —(CR XV-15 R XV-16 ) b XV —, where b XV is 0 or 1
p) —CR XV-15 ═CR XV-15 —,
q) —N═N—Y XV —,
r) —Y XV —N═N—,
s) —Y XV —N═CR XV-15 —, or
t) —CR XV-15 R XV-16 —Y XV —CR XV-15 R XV-16 —CR XV-15 R XV-16 —;
E XV is CR XV-8 or nitrogen;
J XV is CR XV-15 or nitrogen;
K XV is
a) —(CR XV-15 R XV-16 ) a XV —, where a XV is 2 or 3, or
b) —CR XV-15 ═CR XV-15 —;
L XV is
a) —(CR XV-15 R XV-16 ) a XV —, where a XV is 2 or 3, or
b) —Y XV —(CR XV-15 R XV-16 )—(CR XV-15 R XV-16 )—;
Y XV is oxygen, S(O) m XV , or NR XV-7 ;
with the provisos that:
when W XV is of formula W1 XV ; G XV is C 1-4 alkyl which is fully saturated and is substituted by hydroxy or morpholinyl, in which morpholinyl is attached through nitrogen; A XV is CR XV-4 ; B XV is CR XV-5 ; and R XV-8 is hydrogen then at least one of R XV-13 , R XV-14 , or R XV-7 is not hydrogen or C 1-7 alkyl;
when W XV is of formula W1 XV , A XV is CR XV-4 , B XV is CR XV-5 , D XV is —Y XV —CR XV-13 R XV-14 —CR XV-13 R XV-14 —, and R XV-8 is hydrogen then Y XV is not oxygen;
when W XV is of formula W1 XV , A XV is CR XV-4 , and B XV is CR XV-5 then D XV is not —CR XV-15 ═CR XV-15 —;
R XV-4 is H, halogen, or C 1-4 alkyl optionally substituted by one to three halogens;
R XV-5 is
a) H,
b) halo,
c) OR XV-12 ,
d) SR XV-12 ,
e) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XV-12 , SR XV-12 , NR XV-10 R XV-11 , or halo,
f) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen,
g) (C═O)R XV-9 ,
h) S(O) m XV R XV-9 ,
i) (C═O)OR XV-2 ,
j) NHSO 2 R XV-9 ,
k) nitro, or
l) cyano;
R XV-7 is
a) H,
b) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XV-12 , SR XV-12 , NR XV-10 R XV-11 , or halo,
c) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XV-12 , SR XV-12 , or NR XV-10 R XV-11 , OR XV-12 , SR XV-12 , or NR XV-10 R XV-11 ,
d) aryl XV ,
e) het XV ,
f) (C═O)R XV-9 , or
g) S(O) m XV R XV-9 ;
R XV-8 is
a) H,
b) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more substituents selected from OR XV-12 , SR XV-12 , NR XV-10 R XV-11 , or halo,
c) OR XV-12 , or
d) SR XV-12 ;
R XV-9 is
a) C 1-7 alkyl optionally substituted by OR XV-12 or NR XV-2 R XV-2 ,
b) C 3-8 cycloalkyl optionally substituted by OR XV-12 or NR XV-2 R XV-2 ,
c) NR XV-10 R XV-11 ,
d) aryl XV , or
e) het XV , wherein said hetXV is bound through a carbon atom;
R XV-10 and R XV-11 are independently
a) H,
b) aryl XV ,
c) C 1-7 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from CONR XV-2 R XV-2 , CO 2 R XV-2 , het XV , aryl XV , cyano, or halo,
d) C 2-7 alkyl which may be partially unsaturated and is substituted by one or more substituents selected from NR XV-2 R XV-2 , OR XV-2 , or SR XV-2 ,
e) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XV-10 , SR XV-2 , or NR XV-2 R XV-2 , or
f) R XV-10 and R XV-11 together with the nitrogen to which they are attached form a het XV ;
R XV-12 is
a) H,
b) aryl XV ,
c) het XV ,
d) C 1-7 alkyl optionally substituted by arylXV, or halogen,
e) C 2-7 alkyl substituted by OR XV-2 , SR XV-2 , or NR XV-2 R XV-2 , or
f) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XV-2 , SR XV-2 , or NR XV-2 R XV-2 ;
R XV-13 , R XV-14 , R XV-15 , and R XV-16 are independently
a) H
b) C 1-7 alkyl which may be partially unsaturated and optionally substituted by one or more OR XV-12 , SR XV-12 , NR XV-10 R XV-11 , or halo groups,
c) C 3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from halogen, OR XV-12 , SR XV-12 , or NR XV-10 R XV-11 ,
d) aryl XV ,
e) het XV , wherein said het XV is bound through a carbon atom,
f) OR XV-12 ,
g) SR XV-12 ,
h) NR XV-10 R XV-11 ;
i) (C═O)OR XV-2 , or
j) R XV-13 and R XV-14 or R XV-15 and R XV-16 together with the carbon to which they are attached form (C═O);
each m XV is independently 0, 1 or 2;
each n XV is independently 1 or 3;
aryl XV is a phenyl radical or an ortho-fused bicyclic carbocyclic radical wherein at least one ring is aromatic, and aryl XV may be optionally substituted with one or more substituents selected from halo, OH, cyano, NR XV-2 R XV-2 , CO 2 R XV-2 , CF 3 , C 1-6 alkoxy, and C 1-6 alkyl which maybe further substituted by one to three SR XV-2 , NR XV-2 R XV-2 , OR XV-2 , or CO 2 R XV-2 groups;
het XV is a four- (4), five- (5), six- (6), or seven- (7) membered saturated or unsaturated heterocyclic ring having 1, 2, or 3 heteroatoms selected from oxygen, sulfur, or nitrogen, which is optionally fused to a benzene ring, or any bicyclic heterocycle group, and het XV may be optionally substituted with one or more substituents selected from halo, OH, cyano, phenyl, CO 2 R XV-2 , CF 3 , C 1-6 alkoxy, oxo, oxime, and C 1-6 alkyl which may be further substituted by one to three SR XV-2 , NR XV-2 R XV-2 , OR XV-2 , or CO 2 R XV-2 groups;
halo or halogen is F, Cl, Br, I;
1 represents the point of attachment between W XV and GXV;
2 represents the point of attachment between W XV and the carbonyl group of Formula (XV),
16 . The method of claim 15 , wherein the compound administered is selected from the group consisting of
(1) N-(4-chlorobenzyl)-8-(4-morpholinylmethyl)-6-oxo-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide; (2) N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-6-oxo-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide; (3) N-(4-chlorobenzyl)-8-(3-hydroxypropyl)-6-oxo-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide; (4) 1-amino-N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide; (5) 1-amino-N-(4-chlorobenzyl)-8-(3-hydroxypropyl)-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide; (6) 1-amino-N-(4-chlorobenzyl)-8-(4-morpholinylmethyl)-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide; (7) N-(4-chlorobenzyl)-2-(hydroxymethyl)-8-(3-hydroxy-1-propynyl)-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide; (8) N-(4-chlorobenzyl)-8-(3-hydroxyprop-1-ynyl)-2,2-dimethyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide; (9) 3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide; (10) 3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide; (11) 3-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide; (12) 3-benzyl-N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide; (13) N-(4-chlorobenzyl)-9-(3-hydroxyprop-1-ynyl)-3-methyl-7-oxo-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide; (14) 3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide; (15) 3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide; (16) 3-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide; (17) 3-benzyl-N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-7-oxo-2,3-dihydro-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide; (18) N-(4-chlorobenzyl)-3-methyl-9-(morpholin-4-ylmethyl)-7-oxo-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxamide; (19) N-(4-chlorobenzyl)-3-methyl-7-oxo-9-(tetrahydro-2H-pyran-4-ylmethyl)-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxamide; (20) N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-3-methyl-7-oxo-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxamide; (21) N-(4-chlorobenzyl)-9-(3-hydroxyprop-1-ynyl)-3-methyl-7-oxo-7H-[1,4]thiazino [2,3,4-ij]quinoline-6-carboxamide; (22) N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-pyridin-3-yl-7H-[1,4]thiazino[2,3,4-ij]quinoline-6-carboxamide; (23) N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-3-phenyl-1H,7H-[1,3]oxazino[5,4,3-ij]quinoline-6-carboxamide; (24) N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-3-phenyl-1H,7H-[1,3]oxazino[5,4,3-ij]quinoline-6-carboxamide; (25) N-(4-chlorobenzyl)-7-oxo-3-phenyl-9-(tetrahydro-2H-pyran-4-ylmethyl)-1H,7H-[1,3]oxazino [5,4,3-ij]quinoline-6-carboxamide; (26) N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-3-phenyl-1H,7H-[1,3]oxazino[5,4,3-ij]quinoline-6-carboxamide; (27) N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-1-methyl-7-oxo-3-phenyl-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (28) N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-1-methyl-7-oxo-3-phenyl-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (29) N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-1-methyl-7-oxo-3-phenyl-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (30) N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-1-methyl-7-oxo-3-phenyl-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (31) N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-2,3,7-trioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (32) N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-2,3,7-trioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (33) N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-2,3,7-trioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (34) N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (35) N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (36) N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-3,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (37) N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-3,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (38) N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-3,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (39) N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (40) N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-1-methyl-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (41) 3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-1-methyl-7-oxo-2,3-dihydro-1H,7H-[1,2,4]triazino[5,6,1-ij]quinoline-6-carboxamide; (42) 3-benzyl-N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-1-methyl-7-oxo-2,3-dihydro-1H,7H-[1,2,4]triazino[5,6,1-ij]quinoline-6-carboxamide; (43) 3-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-1-methyl-7-oxo-2,3-dihydro-1H,7H-[1,2,4]triazino[5,6,1-ij]quinoline-6-carboxamide; (44) 3-benzyl-N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-1-methyl-7-oxo-2,3-dihydro-1H,7H-[1,2,4]triazino[5,6,1-ij]quinoline-6-carboxamide; (45) 1-benzyl-N-(4-chlorobenzyl)-5-(3-hydroxy-1-propynyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide; (46) 1-benzyl-N-(4-chlorobenzyl)-5-(3-hydroxypropyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide; (47) 1-benzyl-N-(4-chlorobenzyl)-5-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide; (48) 1-benzyl-N-(4-chlorobenzyl)-5-(tetrahydro-2H-pyran-4-ylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide; (49) N-(4-Chlorobenzyl)-5-(3-hydroxyprop-1-ynyl)-1-methyl-7-oxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide; (50) N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-3-phenyl-1H,7H-[1,3]thiazino[5,4,3-ij]quinoline-6-carboxamide; (51) N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-3-phenyl-1H,7H-[1,3]thiazino[5,4,3-ij]quinoline-6-carboxamide; (52) N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-7-oxo-3-phenyl-1H,7H-[1,3]thiazino[5,4,3-ij]quinoline-6-carboxamide; (53) N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-3-phenyl-1H,7H-[1,3]thiazino[5,4,3-ij]quinoline-6-carboxamide; (54) N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-2-methyl-7-oxo-3-phenyl-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide; (55) N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-2-methyl-7-oxo-3-phenyl-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide; (56) N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-2-methyl-7-oxo-3-phenyl-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide; (57) N-(4-chlorobenzyl)-9-(tetrahydro-2H-pyran-4-ylmethyl)-2-methyl-7-oxo-3-phenyl-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide; (58) 2-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide; (59) 2-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-3,7-dioxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide; (60) N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-2-(4-morpholinyl)-7-oxo-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide; (61) N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-2-(4-morpholinyl)-7-oxo-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide; (62) N-(4-chlorobenzyl)-2-(4-morpholinyl)-9-(4-morpholinylmethyl)-7-oxo-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide; (63) N-(4-chlorobenzyl)-2-(4-morpholinyl)-7-oxo-9-(tetrahydro-2H-pyran-4-ylmethyl)-7H-[1,3,4]thiadiazino[6,5,4-ij]quinoline-6-carboxamide; (64) N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-1H,7H-pyrazino[3,2,1-ij][1,7]naphthyridine-6-carboxamide; (65) N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-1H,7H-pyrazino[3,2,1-ij][1,7]naphthyridine-6-carboxamide; (66) N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-1H,7H-pyrazino[3,2,1-ij][1,7]naphthyridine-6-carboxamide; (67) N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-7H-[1,4]thiazino[2,3,4-ij][1,7]naphthyridine-6-carboxamide; (68) N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]thiazino[2,3,4-ij][1,7]naphthyridine-6-carboxamide; (69) N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-7H-[1,4]thiazino[2,3,4-ij][1,7]naphthyridine-6-carboxamide; (70) N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij][1,7]naphthyridine-6-carboxamide; (71) N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij][1,7]naphthyridine-6-carboxamide; (72) N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij][1,7]naphthyridine-6-carboxamide; (73) N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-3,7-dioxo-3H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (74) N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-3,7-dioxo-3H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (75) N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-3,7-dioxo-3H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (76) N-(4-chlorobenzyl)-2-[(4-chlorobenzyl)amino]-9-(4-morpholinylmethyl)-7-oxo-3H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (77) 2-(benzylamino)-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-3H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (78) N-(4-chlorobenzyl)-10-(3-hydroxypropyl)-2,4,8-trioxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamide; (79) N-(4-chlorobenzyl)-10-(3-hydroxy-1-propynyl)-2,4,8-trioxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamide; (80) N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-2,4,8-trioxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamide; (81) N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-2,8-dioxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamide; (82) N-(4-chlorobenzyl)-8-(4-morpholinylmethyl)-2,6-dioxo-1,2-dihydro-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide; (83) N-(4-chlorobenzyl)-8-(3-hydroxy-1-propynyl)-2,6-dioxo-1,2-dihydro-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide; (84) N-(4-chlorobenzyl)-8-(3-hydroxypropyl)-2,6-dioxo-1,2-dihydro-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide; (85) N-(4-chlorobenzyl)-8-(4-morpholinylmethyl)-2,6-dioxo-1-[2-(1-piperidinyl)ethyl]-1,2-dihydro-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide; (86) N-(4-chlorobenzyl)-1-[2-(4-methyl-1-piperazinyl)ethyl]-8-(4-morpholinylmethyl)-2,6-dioxo-1,2-dihydro-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide; (87) N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-8-oxo-3,4-dihydro-2H,8H-[1,4]oxazepino[2,3,4-ij]quinoline-7-carboxamide; (88) N-(4-chlorobenzyl)-3-methyl-9-(morpholin-4-ylmethyl)-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide; (89) N-(4-chlorobenzyl)-3-methyl-7-oxo-9-(tetrahydro-2H-pyran-4-ylmethyl)-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide; (90) N-(4-chlorobenzyl)-9-(3-hydroxypropyl)-3-methyl-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide; (91) N-(4-chlorobenzyl)-9-(3-hydroxyprop-1-ynyl)-3-methyl-7-oxo-7H-[1,4]oxazino [2,3,4-ij]quinoline-6-carboxamide; (92) N-(4-chlorobenzyl)-9-(morpholin-4-ylmethyl)-7-oxo-2-pyridin-3-yl-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide; (93) 2-benzyl-N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-3,8-dioxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[6,7,1-ij]quinoline-7-carboxamide; (94) N-(4-chlorobenzyl)-5-(3-hydroxypropyl)-4,7-dioxo-1,2-dihydro-4H,7H-imidazo[1,2,3-ij][1,8]naphthyridine-8-carboxamide; (95) N-(4-chlorobenzyl)-5-(4-morpholinylmethyl)-4,7-dioxo-1,2-dihydro-4H,7H-imidazo[1,2,3-ij][1,8]naphthyridine-8-carboxamide; (96) N-(4-chlorobenzyl)-5-(3-hydroxy-1-propynyl)-4,7-dioxo-1,2-dihydro-4H,7H-imidazo[1,2,3-iji][1,8]naphthyridine-8-carboxamide; (97) N-(4-chlorobenzyl)-6-(4-morpholinylmethyl)-3-oxo-9,10-dihydro-3H,8H-pyrido [3,2,1-ij]quinoline-2-carboxamide; (98) N-(4-chlorobenzyl)-3-methyl-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide hydrobromide; and pharmaceutically acceptable salts thereof.
17 . The method according to claim 15 , wherein the compound administered is selected from the group consisting of
(1) N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-8-oxo-3,4-dihydro-2H,8H-[1,4]oxazepino [2,3,4-ij]quinoline-7-carboxamide; (2) N-(4-chlorobenzyl)-8-(4-morpholinylmethyl)-2,6-dioxo-1,2-dihydro-6H-imidazo[4,5,1-ij]quinoline-5-carboxamide; (3) N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (4) N-(4-chlorobenzyl)-2-[(4-chlorobenzyl)amino]-9-(4-morpholinylmethyl)-7-oxo-3H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (5) N-(4-chlorobenzyl)-2-(hydroxymethyl)-8-(3-hydroxy-1-propynyl)-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide; (6) N-(4-chlorobenzyl)-8-(3-hydroxyprop-1-ynyl)-2,2-dimethyl-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide; (7) N-(4-chlorobenzyl)-6-(morpholin-4-ylmethyl)-3-oxo-9,10-dihydro-3H,8H-pyrido[3,2,1-ij]quinoline-2-carboxamide; (8) N-(4-chlorobenzyl)-3-methyl-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide hydrobromide; (9) N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-2,8-dioxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamide; (10) 2-(benzylamino)-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-3H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (11) N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-1-methyl-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (12) 2-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide; (13) 2-benzyl-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-3,7-dioxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]quinazoline-6-carboxamide; (14) 2-benzyl-N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-3,8-dioxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[6,7,1-ij]quinoline-7-carboxamide; (15) N-(4-chlorobenzyl)-9-(3-hydroxyprop-1-ynyl)-3-methyl-7-oxo-2,3-dihydro-7H-[1,3,4]oxadiazino[6,5,4-ij]quinoline-6-carboxamide; (16) N-(4-Chlorobenzyl)-5-(3-hydroxyprop-1-ynyl)-1-methyl-7-oxo-2,3-dihydro-1H,7H-pyrido[3,2,1-ij]cinnoline-8-carboxamide; and pharmaceutically acceptable salts thereof.
18 . The method according to claim 15 , wherein the compound administered is selected from the group consisting of
(1) N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-8-oxo-3,4-dihydro-2H,8H-[1,4]oxazepino [2,3,4-ij]quinoline-7-carboxamide; (2) N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (3) N-(4-chlorobenzyl)-3-methyl-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide hydrobromide; (4) N-(4-chlorobenzyl)-10-(4-morpholinylmethyl)-2,8-dioxo-1,2,3,4-tetrahydro-8H-[1,4]diazepino[3,2,1-ij]quinoline-7-carboxamide; (5) 2-(benzylamino)-N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-7-oxo-3H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (6) N-(4-chlorobenzyl)-9-(3-hydroxy-1-propynyl)-1-methyl-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; and pharmaceutically acceptable salts thereof.
19 . The method according to claim 15 , wherein the compound administered is selected from the group consisting of
(1) N-(4-chlorobenzyl)-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide; (2) N-(4-chlorobenzyl)-3-methyl-9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxamide hydrobromide; and pharmaceutically acceptable salts thereof.
20 . The method according to claim 1 , wherein said mammal is a human.
21 . The method according to claim 1 , wherein said mammal is a livestock or companion animal.
22 . The method according to claim 1 , wherein the amount administered is from about 0.1 to about 300 mg/kg of body weight.
23 . The method according to claim 1 , wherein the amount administered is from about 1.0 to about 30 mg/kg of body weight.
24 . The method according to claim 1 , wherein the compound is administered parenterally, topically, intravaginally, orally, or rectally.Join the waitlist — get patent alerts
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